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"Lewis, David M. (David Malcolm)"
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Management of Malignant Pleural Effusions. An Official ATS/STS/STR Clinical Practice Guideline
This Guideline, a collaborative effort from the American Thoracic Society, Society of Thoracic Surgeons, and Society of Thoracic Radiology, aims to provide evidence-based recommendations to guide contemporary management of patients with a malignant pleural effusion (MPE).
A multidisciplinary panel developed seven questions using the PICO (Population, Intervention, Comparator, and Outcomes) format. The GRADE (Grading of Recommendations, Assessment, Development and Evaluation) approach and the Evidence to Decision framework was applied to each question. Recommendations were formulated, discussed, and approved by the entire panel.
The panel made weak recommendations in favor of: 1) using ultrasound to guide pleural interventions; 2) not performing pleural interventions in asymptomatic patients with MPE; 3) using either an indwelling pleural catheter (IPC) or chemical pleurodesis in symptomatic patients with MPE and suspected expandable lung; 4) performing large-volume thoracentesis to assess symptomatic response and lung expansion; 5) using either talc poudrage or talc slurry for chemical pleurodesis; 6) using IPC instead of chemical pleurodesis in patients with nonexpandable lung or failed pleurodesis; and 7) treating IPC-associated infections with antibiotics and not removing the catheter.
These recommendations, based on the best available evidence, can guide management of patients with MPE and improve patient outcomes.
Journal Article
Pandemic, Epidemic, Endemic: B Cell Repertoire Analysis Reveals Unique Anti-Viral Responses to SARS-CoV-2, Ebola and Respiratory Syncytial Virus
Immunoglobulin gene heterogeneity reflects the diversity and focus of the humoral immune response towards different infections, enabling inference of B cell development processes. Detailed compositional and lineage analysis of long read IGH repertoire sequencing, combining examples of pandemic, epidemic and endemic viral infections with control and vaccination samples, demonstrates general responses including increased use of IGHV4-39 in both Zaire Ebolavirus (EBOV) and COVID-19 patient cohorts. We also show unique characteristics absent in Respiratory Syncytial Virus or yellow fever vaccine samples: EBOV survivors show unprecedented high levels of class switching events while COVID-19 repertoires from acute disease appear underdeveloped. Despite the high levels of clonal expansion in COVID-19 IgG1 repertoires there is a striking lack of evidence of germinal centre mutation and selection. Given the differences in COVID-19 morbidity and mortality with age, it is also pertinent that we find significant differences in repertoire characteristics between young and old patients. Our data supports the hypothesis that a primary viral challenge can result in a strong but immature humoral response where failures in selection of the repertoire risk off-target effects.
Journal Article
Multiple Common Susceptibility Variants near BMP Pathway Loci GREM1, BMP4, and BMP2 Explain Part of the Missing Heritability of Colorectal Cancer
Genome-wide association studies (GWAS) have identified 14 tagging single nucleotide polymorphisms (tagSNPs) that are associated with the risk of colorectal cancer (CRC), and several of these tagSNPs are near bone morphogenetic protein (BMP) pathway loci. The penalty of multiple testing implicit in GWAS increases the attraction of complementary approaches for disease gene discovery, including candidate gene- or pathway-based analyses. The strongest candidate loci for additional predisposition SNPs are arguably those already known both to have functional relevance and to be involved in disease risk. To investigate this proposition, we searched for novel CRC susceptibility variants close to the BMP pathway genes GREM1 (15q13.3), BMP4 (14q22.2), and BMP2 (20p12.3) using sample sets totalling 24,910 CRC cases and 26,275 controls. We identified new, independent CRC predisposition SNPs close to BMP4 (rs1957636, P = 3.93×10(-10)) and BMP2 (rs4813802, P = 4.65×10(-11)). Near GREM1, we found using fine-mapping that the previously-identified association between tagSNP rs4779584 and CRC actually resulted from two independent signals represented by rs16969681 (P = 5.33×10(-8)) and rs11632715 (P = 2.30×10(-10)). As low-penetrance predisposition variants become harder to identify-owing to small effect sizes and/or low risk allele frequencies-approaches based on informed candidate gene selection may become increasingly attractive. Our data emphasise that genetic fine-mapping studies can deconvolute associations that have arisen owing to independent correlation of a tagSNP with more than one functional SNP, thus explaining some of the apparently missing heritability of common diseases.
Journal Article
Large-scale phenotyping of patients with long COVID post-hospitalization reveals mechanistic subtypes of disease
One in ten severe acute respiratory syndrome coronavirus 2 infections result in prolonged symptoms termed long coronavirus disease (COVID), yet disease phenotypes and mechanisms are poorly understood
1
. Here we profiled 368 plasma proteins in 657 participants ≥3 months following hospitalization. Of these, 426 had at least one long COVID symptom and 233 had fully recovered. Elevated markers of myeloid inflammation and complement activation were associated with long COVID. IL-1R2, MATN2 and COLEC12 were associated with cardiorespiratory symptoms, fatigue and anxiety/depression; MATN2, CSF3 and C1QA were elevated in gastrointestinal symptoms and C1QA was elevated in cognitive impairment. Additional markers of alterations in nerve tissue repair (SPON-1 and NFASC) were elevated in those with cognitive impairment and SCG3, suggestive of brain–gut axis disturbance, was elevated in gastrointestinal symptoms. Severe acute respiratory syndrome coronavirus 2-specific immunoglobulin G (IgG) was persistently elevated in some individuals with long COVID, but virus was not detected in sputum. Analysis of inflammatory markers in nasal fluids showed no association with symptoms. Our study aimed to understand inflammatory processes that underlie long COVID and was not designed for biomarker discovery. Our findings suggest that specific inflammatory pathways related to tissue damage are implicated in subtypes of long COVID, which might be targeted in future therapeutic trials.
Openshaw and colleagues find myeloid inflammation and complement activation signatures in patients with long COVID who were previously hospitalized.
Journal Article
Cognitive Behavior Therapy for Depersonalization-Derealization Disorder (CBT-f-DDD): a feasibility randomized trial
Background
Depersonalization-derealization disorder (DDD) is characterized by feelings of “unreality” about the self and/or external world. Cognitive Behavioral Therapy adapted for DDD (CBT-f-DDD) has been effective in published clinical audits. This study aimed to provide feasibility and acceptability data.
Methods
An individually randomized design of CBT-f-DDD versus Treatment as Usual (TAU) was carried out with adult DDD participants from NHS Trusts in London. The CBT-f-DDD group received individual sessions over a 6-month period from CBT therapists. Qualitative interviews were conducted with CBT-f-DDD participants and their clinicians. Eight feasibility objectives were evaluated (recruitment, retention, resources, representativeness, acceptability of study design and intervention, preliminary responses to intervention, and health economics).
Results
Thirty participants with DDD were recruited over 13 months. Only 63% completed the final assessment, so retention needs improvement. Resources were acceptable. The sample was comparable to previous studies, although younger, with a shorter duration of DDD and lower mean DDD scores. In a post-study questionnaire, no aspect of the study or treatment was rated unacceptable; however, some areas need improvement. Qualitative interviews with participants and clinicians recorded positive responses to CBT-f-DDD. Those in the CBT arm had a mean decrease of 16.9 points (SD 43.6) on the Cambridge Depersonalization Scale versus a mean decrease of 5.5 points (SD = 25.0) for the TAU arm. Health economics analyses found that CBT-f-DDD saved £153 per person. Participants reported an additional 0.08 Quality-Adjusted Life Years at low cost.
Conclusions
This study suggests that a subsequent RCT for CBT-f-DDD is feasible and represents the first step in the process of establishing evidence-based treatments for DDD. However, refinements to the current design and delivery were indicated for a future fully powered definitive RCT of CBT-f-DDD.
Trial registration
ISRCTN, ISRCTN97686121. Retrospectively registered 5 January 2023: https://doi.org/10.1186/ISRCTN97686121
Journal Article
Lung Cancer Recurrence Risk Prediction through Integrated Deep Learning Evaluation
Background: Prognostic risk factors for completely resected stage IA non-small-cell lung cancers (NSCLCs) have advanced minimally over recent decades. Although several biomarkers have been found to be associated with cancer recurrence, their added value to TNM staging and tumor grade are unclear. Methods: Features of preoperative low-dose CT image and histologic findings of hematoxylin- and eosin-stained tissue sections of resected lung tumor specimens were extracted from 182 stage IA NSCLC patients in the National Lung Screening Trial. These features were combined to predict the risk of tumor recurrence or progression through integrated deep learning evaluation (IDLE). Added values of IDLE to TNM staging and tumor grade in progression risk prediction and risk stratification were evaluated. Results: The 5-year AUC of IDLE was 0.817 ± 0.037 as compared to the AUC = 0.561 ± 0.042 and 0.573 ± 0.044 from the TNM stage and tumor grade, respectively. The IDLE score was significantly associated with cancer recurrence (p < 0.0001) even after adjusting for TNM staging and tumor grade. Synergy between chest CT image markers and histological markers was the driving force of the deep learning algorithm to produce a stronger prognostic predictor. Conclusions: Integrating markers from preoperative CT images and pathologist’s readings of resected lung specimens through deep learning can improve risk stratification of stage 1A NSCLC patients over TNM staging and tumor grade alone. Our study suggests that combining markers from nonoverlapping platforms can increase the cancer risk prediction accuracy.
Journal Article
Summary for Clinicians: Clinical Practice Guideline for Management of Malignant Pleural Effusions
Because the average survival of patients with MPE is 4 to 7 months (3), treatment should aim to relieve dyspnea in a minimally invasive manner and prevent the need for multiple procedures. The use of ultrasound guidance reduced the risk of pneumothorax after thoracentesis for malignant effusions (1.0% vs. 8.9%; relative risk [RR], 0.10; 95% confidence interval [CI], 0.03-0.37). On the basis of the reduced length of hospital stay and low observed incidence of complications associated with IPCs, as well as abundant clinical experience that chemical pleurodesis is rarely effective in the setting of nonexpandable lung, the panel recommended IPCs over chemical pleurodesis. 3 Porcel JM,GasolA, BielsaS, Civit C, Light RW, Salud A. Clinical features and survival of lung cancer patients with pleural effusions.
Journal Article
Five endometrial cancer risk loci identified through genome-wide association analysis
Amanda Spurdle, Ian Tomlinson, Douglas Easton and colleagues conduct a GWAS meta-analysis and identify five new risk loci for endometrial cancer. Functional studies show that one risk-associated SNP is located in an active chromatin region that interacts with the
KLF5
promoter.
We conducted a meta-analysis of three endometrial cancer genome-wide association studies (GWAS) and two follow-up phases totaling 7,737 endometrial cancer cases and 37,144 controls of European ancestry. Genome-wide imputation and meta-analysis identified five new risk loci of genome-wide significance at likely regulatory regions on chromosomes 13q22.1 (rs11841589, near
KLF5
), 6q22.31 (rs13328298, in
LOC643623
and near
HEY2
and
NCOA7
), 8q24.21 (rs4733613, telomeric to
MYC
), 15q15.1 (rs937213, in
EIF2AK4
, near
BMF
) and 14q32.33 (rs2498796, in
AKT1
, near
SIVA1
). We also found a second independent 8q24.21 signal (rs17232730). Functional studies of the 13q22.1 locus showed that rs9600103 (pairwise
r
2
= 0.98 with rs11841589) is located in a region of active chromatin that interacts with the
KLF5
promoter region. The rs9600103[T] allele that is protective in endometrial cancer suppressed gene expression
in vitro
, suggesting that regulation of the expression of
KLF5
, a gene linked to uterine development, is implicated in tumorigenesis. These findings provide enhanced insight into the genetic and biological basis of endometrial cancer.
Journal Article
